1. Field of the Invention
The present invention concerns antitumor compounds. More particularly, the invention provides novel taxane derivatives, pharmaceutical compositions thereof, and their use as antitumor agents.
2. Background Art
Taxol.RTM. (paclitaxel) is a natural product extracted from the bark of Pacific yew trees, Taxus brevifolia. It has been shown to have excellent antitumor activity in in vivo animal models, and recent studies have elucidated its unique mode of action, which involves abnormal polymerization of tubulin and disruption of mitosis. It was recently approved for the treatment of ovarian cancer; and studies involving breast, colon, and lung cancers have shown promising results. The results of paclitaxel clinical studies are reviewed in Rowinsky and Donehower, "The Clinical Pharmacology and Use of Antimicrotubule Agents in Cancer Chemotherapeutics" Pharmac. Ther., 52:35-84, 1991.
Recently, a semi-synthetic analog of paclitaxel named Taxotere.RTM. has also been found to have good antitumor activity in animal models. Taxotere.RTM. is also currently undergoing clinical trials in Europe and the United States. The structures of paclitaxel and Taxotere.RTM. are shown below; the conventional numbering system of the paclitaxel molecule is provided. ##STR1## Taxol.RTM.: R=Ph; R'=acetyl Taxotere.RTM.: R=t-butoxy; R'=hydrogen
One drawback of paclitaxel is its very limited water solubility requiring it to be formulated in nonaqueous pharmaceutical vehicles. One commonly used carrier is Cremophor EL which may itself have undesirable side effects in man. Accordingly, a number of research teams have prepared water-soluble derivatives of paclitaxel which are disclosed in the following references:
(a) Haugwitz et al, U.S. Pat. No. 4,942,184; PA1 (b) Kingston et al, U.S. Pat. No. 5,059,699; PA1 (c) Stella et al, U.S. Pat. No. 4,960,790; PA1 (d) European Patent Application 0,558,959 A1 published Sep. 8, 1993; PA1 (e) Vyas et al, Bioorganic & Medicinal Chemistry Letters, 1993, 3:1357-1360; and PA1 (f) Nicolaou et al, Nature, 1993, 364:464-466
Compounds of the present invention are phosphonooxymethyl ethers of taxane derivatives and pharmaceutically acceptable salts thereof. The water solubility of the salts facilitates preparation of pharmaceutical formulations.